Journal of Autoimmunity
Journal of Autoimmunity
5 years ago

Nuclear orphan receptor NR2F6 directly antagonizes NFAT and RORγt binding to the Il17a promoter

Interleukin-17A (IL-17A) is the signature cytokine produced by Th17 CD4+ T cells and has been tightly linked to autoimmune pathogenesis. In particular, the transcription factors NFAT and RORγt are known to activate Il17a transcription, although the detailed mechanism of action remains incompletely understood. Here, we show that the nuclear orphan receptor NR2F6 can attenuate the capacity of NFAT to bind to critical regions of the Il17a gene promoter. In addition, because NR2F6 binds to defined hormone response elements (HREs) within the Il17a locus, it interferes with the ability of RORγt to access the DNA. Consistently, NFAT and RORγt binding within the Il17a locus were enhanced in Nr2f6-deficient CD4+ Th17 cells but decreased in Nr2f6-overexpressing transgenic CD4+ Th17 cells. Taken together, our findings uncover an example of antagonistic regulation of Il17a transcription through the direct reciprocal actions of NR2F6 versus NFAT and RORγt.

Highlights

► NR2F6 controls IL-17A expression in Th17 cells and attenuates EAE. ► NR2F6 counteracts NFAT and RORγt binding to the Il17a promoter. ► NR2F6 is released from the Il17a promoter upon TCR stimulation. ► NR2F6 acts as a gatekeeper for the transcriptional regulation of Il17a in Th17 cells.

Publisher URL: www.sciencedirect.com/science

DOI: S0896841112001035

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